Malaria and the liver: immunological hide-and-seek or subversion of immunity from within?

Abstract

During the pre-erythrocytic asymptomatic phase of malarial infection, sporozoites develop transiently inside less than 100 hepatocytes that subsequently release thousands of merozoites. Killing of these hepatocytes by cytotoxic T cells (CTLs) confers protection to subsequent malarial infection, suggesting that this bottleneck phase in the parasite life cycle can be targeted by vaccination. During natural transmission, although some CTLs are generated in the skin draining lymph nodes, they are unable to eliminate the parasite, suggesting that the liver is important for the sporozoite to escape immune surveillance. The contribution of the organ to this process is unclear. Based on the known ability of several hepatic antigen-presenting cells (APCs) to induce primary activation of CD8 T cells and tolerance, malarial antigens presented by both infected hepatocytes and/or hepatic cross-presenting APCs should result in tolerance. However, our latest model predicts that due to the low frequency of infected hepatocytes, some T cells recognizing sporozoite epitopes with high affinity should differentiate into CTLs. In this review, we discuss two possible models to explain why CTLs generated in the liver and skin draining lymph nodes are unable to eliminate the parasite: (1) sporozoites harness the tolerogenic property of the liver; (2) CTLs are not tolerized but fail to detect infected cells due to sparse infection of hepatocytes and the very short liver stage. We propose that while malaria sporozoites might use the ability of the liver to tolerize both naive and effector cells, they have also developed strategies to decrease the probability of encounter between CTLs and infected liver cells. Thus, we predict that to achieve protection, vaccination strategies should aim to boost intrahepatic activation and/or increase the chance of encounter between sporozoite-specific CTLs and infected hepatocytes.

Immune outcomes in the liver: Is CD8 T cell fate determined by the environment?

“…and in vivo has been extensively reviewed [45][46][47][48]. In the steady state, most of these liver APCs either do not express or have a low expression of the co-stimulatory molecules CD80 and CD86 [50][51][52][53][54].…”

Protozoan Parasites and Type I IFNs

“…When T cell priming takes place, infected hepatocytes can be eliminated by cytotoxic CD8 T cells. CD8 T cells, IFNγ, and TNF are critical components required for elimination of infected hepatocytes in humans and the mouse model (35). However, the immune response at this stage is insufficient and released merozoites can reach erythrocytes giving rise to blood-stage malaria (35).…”

A prime-boost immunization regimen based on a simian adenovirus 36 vectored multi-stage malaria vaccine induces protective immunity in mice

“…Radiation-attenuated sporozoites have been used to produce sterilizing immunity, but this method remains impractical for widespread use due to logistical constraints [2]. Furthermore, the most advanced malaria vaccine candidate, RTS,S/AS01, has failed to produce long-lived efficacy [6, 7], likely due to lack of CD8 + T cell responses induced and its design based on a single pre-erythrocytic stage antigen target, CSP [8], as a single sporozoite that evades immune responses induced against CSP can produce tens of thousands of blood stage merozoites [2, 9, 10]. Moreover, preclinical murine studies on a vaccine candidate based on two pre-erythrocytic-stage antigens, CSP and the thrombospondin-related adhesive protein (TRAP), have not shown increased efficacy compared to single antigen vaccines [11].…”